Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0221002 (primary hyperparathyroidism)
 4,921 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependent fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.
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PMID:Calcium-sensing receptor and calcimimetic agents. 1063 65

In this study, we report an 84-year-old female proband in a Japanese family with familial hypocalciuric hypercalcemia (FHH) caused by an R648stop mutation in the extracellular calcium-sensing receptor (CaR) gene. At the age of 71 years, she presented with hypercalcemia (11.4 mg/dl), hypocalciuria (Cca/Ccr = 0.003), hypermagnesemia (2.9 mg/dl), and a high-serum parathyroid hormone (PTH) level (midregion PTH, 3225 [160-520] pg/ml). At the age of 74 years, a family screening was carried out and revealed a total of 9 hypercalcemic individuals (all intact PTH values <62 pg/dl) among 17 family members tested, thus, being diagnosed as FHH. Two and one-half of three clearly enlarged parathyroid glands were resected, because persistently high PTH levels (intact PTH, 292 pg/ml; midregion PTH, 5225 pg/ml) and the presence of a markedly enlarged parathyroid gland by several imaging modalities (ultrasonography, computed tomography [CT], magnetic resonance imaging [MRI], and subtraction scintigraphy) suggested coexistent primary hyperparathyroidism (pHPT); however, hypercalcemia persisted postoperatively. Histological and immunohistochemical examination revealed that the resected parathyroid glands showed lipohyperplasia as well as normally expressed Ki67, vitamin D receptor (VDR), and the CaR. Sequence analysis disclosed that the proband and all affected family members had a heterozygous nonsense (R648stop) mutation in the CaR gene. This mutation is located in the first intracellular loop; thus, it would be predicted to produce a truncated CaR having only one transmembrane domain (TMD) and lacking its remaining TMDs, intracellular loops, and C-terminal tail. Western analysis of biotinylated HEK293 cells transiently transfected with this mutant receptor showed cell surface expression of the truncated protein at a level comparable with that of the wild-type CaR. The mutant receptor, however, exhibited no increase in intracellular free calcium concentration (Ca2+i) when exposed to high extracellular calcium concentrations (Ca2+o). The proband's clinical course was complicated because of associated renal tubular acidosis (RTA) and nephrotic syndrome. However, it was unclear whether their association affected the development of elevated serum PTH and parathyroid gland enlargement. This report is the first to show that an R648stop CaR mutation yields a truncated receptor that is expressed on the cell surface but is devoid of biological activity, resulting in FHH.
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PMID:Familial hypocalciuric hypercalcemia caused by an R648stop mutation in the calcium-sensing receptor gene. 1246 11

It has long been recognized that the secretion of PTH by chief cells in the parathyroid gland is regulated by extracellular ionized calcium. The molecular mechanism by which extracellular Ca2+ performs this feat was deduced by the cloning of the extracellular calcium-sensing receptor (CaSR) in 1993 in the laboratories of Brown and Hebert. The CaSR is a G protein-coupled cell surface receptor that belongs to family 3 of the GPCR superfamily. The CaSR senses the extracellular ionic activity of the divalent minerals Ca2+ and Mg2+ and translates this information, via a complex array of cellular signaling pathways, to modify cell and tissue function. Genetic studies have demonstrated that the activity of this receptor determines the steady-state plasma calcium concentration in humans by regulating key elements in the calcium homeostatic system. CaSR agonists (calcimimetics) and antagonists (calcilytics) have been identified and have provided both current and potential therapies for a variety of disorders. Calcimimetics can effectively reduce PTH secretion in all forms of hyperparathyroidism. They are likely to become a major therapy for secondary hyperparathyroidism associated with renal failure and for treatment of certain patients with primary hyperparathyroidism. On the therapeutic horizon are calcilytics that can transiently increase PTH and may prove useful in the treatment of osteoporosis.
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PMID:Therapeutic use of calcimimetics. 1640 54

The extracellular calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that is expressed at multiple sites, including the parathyroids and kidneys. The human CASR gene, located on chromosome 3q21.1, encodes a 1078 amino acid protein. More than 230 different disease-causing mutations of the CaSR have been reported. Loss-of-function mutations lead to three hypercalcemic disorders, which are familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism and primary hyperparathyroidism. Gain-of-function mutations, on the other hand, result in the hypocalcemic disorders of autosomal dominant hypocalcemia and Bartter syndrome type V. Moreover, autoantibodies directed against the extracellular domain of the CaSR have been found to be associated with FHH in some patients, and also in some patients with hypoparathyroidism that may be part of autoimmune polyglandular syndrome type 1. Studies of disease-causing CASR mutations have provided insights into structure-function relationships and highlighted intra-molecular domains that are critical for ligand binding, intracellular signaling, and receptor trafficking.
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PMID:Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. 2385 65